The deposition of amyloid beta 42 amino acid peptide (Axcex242), a toxic cleavage product of the transmembrane amyloid precursor protein (APP), in the brain of patients with Alzheimer""s disease (AD) is thought to play a pathogenic role in the disease. Much evidence is consistent with this hypothesis: (i) the appearance of large numbers of amyloid plaques in the brains of patients with AD, (ii) early onset of AD in persons with trisomy 21, (iii) the early onset of AD in humans with a mutated APP gene, and (iv) the appearance of amyloid plaques in the brain and cognitive impairment in mice expressing a mutant, human APP-transgene. However, at present physicians have no way to directly detect amyloid plaques, leaving an AD diagnosis solely to a neurological examination. Except for family history or APOE4 status, physicians cannot predict who is likely to develop AD. Moreover, until very recently, therapeutic approaches to AD were limited to maintaining cholinergic function, using anti-cholinesterase inhibitors such as Aricept, or to attempt to decrease the generation of AB42 from APP.
Recently, a new paradigm for the therapy of AD was suggested by the finding that immunization of APP transgenic mice with Axcex242 decreased cerebral amyloid deposits. This suggested that immune clearance of Axcex242 from the brain might also be a rational therapeutic approaches to AD. Subsequently Bard""s group reported that the administration of murine anti-amyloid-beta peptide (Axcex242) antibodies to the APP transgenic moused model of Alzheimer""s Disease (AD) decreases cerebral amyloid deposition.
While interesting, these results raised the question: if murine anti-Axcex242 antibodies can prevent amyloid deposition in the brains of APP transgenic mice, what is the relationship to humans? The clinical trial results of treating AD by immunization with Axcex2 peptide dashed hopes for this approach in humans. Volunteers developed r brain inflammation having characteristics of encephalitis or meningitis, prompting by suspension of the trial (Weiss, The Washington Post, Sunday Mar. 2, 2002, p. A3).
Accordingly, a significant need remains to diagnose and treat AD in humans. The present invention addresses this need through the discovery of naturally occurring anti-Axcex2 antibodies that appear to be protective.
There is a need in the art for identifying whether someone is at risk for, or has, a neurological disease or disorder. For example, the only definitive diagnosis for Alzheimer""s Disease occurs upon visual inspection of the brain during autopsy; other than family history or ApoE4 status, there is no way to assess our individuals of developing AD risk. The invention provides a great advance: a method for assessing risk of, including diagnosing, neurological diseases or disorders such as AD, and for effectively clearing amyloid plaques.
The present invention advantageously provides method for assessing risk of a immune deficiency or disorder in a subject, which leads to a neurodegenerative disease or disorder. This method comprises comparing a level of anti-amyloid peptide antibody in a biological sample from a subject to a normal level, wherein a lower level in the biological sample from the subject indicates the presence of the disease or disorder. In a specific embodiment, the disease or disorder is Alzheimer""s Disease (AD); in a further specific embodiment, the amyloid peptide is xcex2-amyloid-42 (Axcex242).
The biological sample can be blood, serum, or plasma.
The normal level can be determined from an average of the level of anti-amyloid peptide antibody in the biological sample from a population of age-matched normal subjects who do not show any symptoms of the immune deficiency or disorder, or from an average of the level of anti-amyloid peptide antibody in the biological sample from a population of all subjects, including subjects who do not show any symptoms of the immune deficiency or disorder, or from a single normal to sample.
In a preferred aspect, the method comprises determining the level of anti-amyloid peptide antibody in the biological sample by immunoassay, e.g., enzyme-linked immunosorbent assay.
In addition, the discovery of naturally occurring anti-Axcex2 antibodies, which presumably cross the blood brain barrier with some facility in order to bind to and affect Axcex2, provides a source of imaging agents, e.g., for position emission tomography (PET) scanning.
The surprising observation that certain neurological diseases or disorders are associated with a deficiency of anti-amyloid antibodies leads to an advantageous method of treating such an immune deficiency or disorder in a subject, which leads to a neurodegenerative disease or disorder. This method comprises administering a therapeutically effective amount of a human anti-amyloid peptide antibody to a subject believed to suffer from the immune deficiency or disorder. For example, the disease or disorder can be Alzheimer""s Disease (AD). In such an embodiment, the amyloid peptide can be xcex2-amyloid-42 (Axcex242).
In a specific embodiment, the antibody is a monoclonal antibody, e.g., a humanized antibody, or an antibody from and EBV transformed cell, preferably obtained from a normal patient. In another embodiment, the antibody is a polyclonal antibody purified from normal or healthy serum. It is also possible to generate such an antibody from combinatorial 1 g phage display libraries, and from xeno mice.
A therapeutically effective amount of the antibody can be an amount that provides a level of the antibody in a biological sample from the subject that is at least the same as or greater than a normal level. The level of therapeutic anti-amyloid peptide antibody in a biological sample can be determined by immunoassay, e.g., enzyme-linked immunosorbent assay. Examples of a biological sample include blood, go serum, or plasma, or cerebral spinal fluid (CSF). In specific embodiments, the normal level is determined from an average of the level of anti-amyloid peptide antibody in the biological sample from a population of age-matched normal subjects or a population of all subjects who do not show any symptoms of the immune deficiency or disorder.